Despite decades of research, the precise etiology and pathophysiological mechanisms underlying persistent developmental stuttering remain unclear. While genetics and neuroimaging research have respectively contributed new knowledge pertaining to possible molecular genetic and neurobiological bases of stuttering, what is presently not clear is how these genetic variants link to stuttering-relevant anomalous neural networks, which may mediate emergence and persistence of stuttering. In this application, we will employ multimodal connectomics analyses of functional and structural neuroimaging data acquired from twins discordant for stuttering (both identical and fraternal twins with only one of the pair who stutters). By combining comprehensive whole brain topological analyses and a powerful discordant twin design, the expected results will be significant, because it will help elucidate, for the first time, the extent of genetic versus environmental influences on brain changes associated with developmental stuttering. The overall objective of this application is to identify the relative influence of genetics and environment on brain structure and function as they pertain to persistent stuttering. The central hypothesis is that, decreased connectivity involving the left auditory-motor and basal ganglia-supplementary motor networks previously reported to be associated with stuttering are likely genetically mediated risk factors, whereas aberrant connections with major intrinsic neural networks that interconnect with these networks may be clarified as environmental risk factors relevant to persistent stuttering. The rationale for the proposed research is that, results from this investigation would lead to a better understanding of the basis for stuttering that not only considers potential mechanisms linking genes to stuttering, but also effects of environmental factors that may modulate stuttering risk. We plan to test our central hypothesis and, thereby, accomplish our overall objective for this project, by pursuing the following specific aims: 1. Identify functional and structural connectivity markers that are associated with environmental risk of persistent stuttering, and 2. Identify functional and structural connectivity markers that are associated with genetic risk of persistent stuttering. The proposed work is innovative, as it should provide comprehensive and more accurate heritable neural markers for persistent stuttering during early childhood. Further, the results generated using this new approach are expected to help differentiate genetic versus environmental risk factors underlying brain-based anomalies that lead to stuttering symptoms during childhood. Understanding these mechanisms of risk for persistent stuttering is essential to our efforts to find markers for early diagnosis and guide future research in identifying neural targets for therapy.